The goal of this project is to develop procedures which will potentiate the activity of current and novel cancer chemotherapeutic agents. Binding, transport, cell membrane composition and agent detoxification are modified in an attempt to direct the active agent to susceptible tumor cells. Investigations are initiated in tissue culture and when applicable are extended to tumor bearing mice. Studies include 1) inhibition kinetics of melphalan transport, where it was found that cytotoxicity of this alkylating agent to the L1210 leukemia cell depends upon its uptake by a high-affinity, Leucine-preferring, amino acid transport system; 2) competitive binding studies with chlorambucil, where agents which compete with this alkylating agent for serum binding can improve cytotoxicity by increasing the availability of free drug and 3) alteration of tumor cell membrane composition, where pretreatment of cells with ergosterol potentiates the cytotoxic action of amphotericin-B. BIBLIOGRAPHIC REFERENCES: Schiffman, F. J., Fisher, J.M. and Rabinovitz, M.: Ergosterol-conferred sensitivity to amphotericin B in cultured L1210 mouse leukemia cells. Biochem. Pharmacol. 26: 177-180, 1977. Vistica, D.T., Toal, J.N. and Rabinovitz, M.: Amino acid conferred resistance to melphalan. Characterization of melphalan transport and cytotoxicity in cultured L1210 murine leukemia cells. Cancer Research, 1977 (in press).